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Drug Dosing in PCRRT

Drug Dosing in PCRRT. Deb Pasko, Pharm.D Pharmacy Clinical Specialist, PICU University of Michigan Health System. CRRT Solute Removal. Lots of things removed by CRRT! Drugs, nutrients… FD&C Blue dye #1… Crit Care Med, Mar 2002. Dialysate is used (lactated Ringers, PD solution, etc)

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Drug Dosing in PCRRT

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  1. Drug Dosing in PCRRT Deb Pasko, Pharm.D Pharmacy Clinical Specialist, PICU University of Michigan Health System

  2. CRRT Solute Removal • Lots of things removed by CRRT! • Drugs, nutrients… FD&C Blue dye #1… • Crit Care Med, Mar 2002

  3. Dialysate is used (lactated Ringers, PD solution, etc) Good for small solute removal (<500 Da) diffusion rate inversely proportional to MW Efficiency of solute removal dependent on Blood flow Dialysate flow Filter type Solute molecular weight Less good for larger solutes (MM, Vancomycin?) Diffusive Therapies

  4. Joy MS, Matzke GR, Frye RF, Palevsky PM. AJKD 1998;31:1019-27.

  5. RRT Drug Removal Mechanisms • Diffusion • Convection • Adsorption • May be important for 2 Microglobulin removal • Especially for PMMA membranes • Rarely important for drugs

  6. Vancomycin overdose • 16 day old full-term infant presented to OSH hypothermia, bradycardia, and hypovolemia. Progressed to develop cardiac arrest, transferred to U of M. Dry wt. 2kg. • Received 3 doses of vancomycin 100mg/kg • Initial vancomycin serum concentration was 195.5 mg/L (desired peak conc ~35mg/L)

  7. Vancomycin overdose case

  8. Hemodialyzer differences: Are they important in CVVHD? Most published drug dosing guidelines assume they are all equal in terms of drug removal most hemofilters are high-permeability with large pores frequently high flux hemodialyzers were used for CRRT Vancomycin CVVHD clearance differences between different hemodialyzers Joy MS, et al. Am J Kidney Dis 1998 Jun;31(6):1019-27

  9. No dialysate, removes plasma water as it seeps through membrane Removes small and large molecules easily as long as they can fit through membrane Protein binding important determinant – sieving coefficient <15,000 Da has potential to be removed substantially Drug removal easy to calculate based on sieving coefficient – usually a function of PPB ultrafiltrate concentration/plasma concentration Convective Therapies (Hemofiltration)

  10. Doses Derived Via Sieving Coefficient • Sieving Coefficient (SC) known for many drugs • SC= UF/A • Comes from CAVH or CVVH data • Assumption often made that SC can be used CVVHD when dialysate rate is low. • Saturation coefficient (Sa) more properly used in CVVHD • SC related to protein binding of drugs • Protein binding may differ in critically ill vs. normals

  11. Sieving Coefficient & Protein Binding

  12. Drug Dosing recommendations based on Sieving Coefficient (SC) • Clearance total = ClCRRT + Cl residual renal + Cl non-renal • SC equations only account for ClCRRT • What about other clearances? • Cl residual renal usually not an issue in CRRT patients • Cl non-rena l not always available for drugs

  13. Non-renal clearance rates of selected drugs in patients with normal renal function and ESRD

  14. CRRT Challenges: Drug Dosing Does CVVH removal = CVVHDF = CVVHD??? Molecular weight determines whether solute diffuses well Vancomycin (MW 1450 Da) Aminoglycosides (MW ~450 Da) High dialysate flow rates don’t allow sufficient time for diffusion Probably not an issue when flow = ~1000ml/1.73m2/hr Does Sieving Coefficient (CVVH) = Saturation Coefficient (CVVHD)???

  15. CRRT Challenges: Drug Dosing NO PEDIATRIC DOSING!!!!!!! Most CRRT dosing guidelines based on CVVH @ UFR of 1000 mL/hr Trend is for higher UFR and HD flows UM uses 2L/1.73m2/hr Higher flow rates now achievable with new machines solute removal (H, HD, HDF) mechanisms

  16. Pediatric CrCl • CLCR = K x L/SCR • Where ClCR = creatinine clearance in ml/min/1.73m2 K = constant of proportionality age specific AgeK LBW ≤ 1yo 0.33 Full-term ≤ 1yo 0.45 2-12 0.55 13-21 female 0.55 13-21 male 0.70

  17. Calculating Total Clearance • Example: • 2yo, 15kg, L = 60cm, SCR = 1.0 mg/dL, K = 0.55 • CrCl = 0.55 x 60/1 = 33ml/min/1.73m2 • However, if anuric renal clearance = zero • PCRRT = CVVHD of 2L/1.73m2/hr, BSA of 0.5 • Qd = ~578ml/hr • (38.5ml/kg, or 9.6ml/min/0.5 BSA, or 33.2ml/min/1.73ml/min) • If this patient was not anuric and had renal fxn as above = 66ml/min/1.73m2, and we need to adjust accordingly

  18. Adjusting doses based on Cl • Using the previous example for vancomycin: • >50ml/min/1.73m2 = q6-8h dosing • 30-50ml/min/1.73m2 = q12h dosing It is easy to under-dose or possibly overdose using this method, need to be careful Is CrCl the most reliable method for children?

  19. What drugs do we care about? • Drugs are “dialyzable” if: • Small MW • Small volume of distribution • Not highly protein bound • Water soluble

  20. Case • 10mof, ALL s/p chemo & BMT x60days, now admitted to unit for increased O2 needs requiring vent support, GVHD gut/liver stage IV and in septic shock. • PE: T 39.1, HR 180, BP 60/30, wt. 8.5kg, Ht 60cm • I/O: 900/50 over past 24hrs (0.24cc/kg/hr) • Baseline Scr = 0.3mg/dL, now 0.6mg/dL • Meds: Dopamine, Cefepime, Gentamicin, Linezolid, Voriconazole, Pentamidine, Hydrocortisone, Protonix, TPN/lipids, Dilaudid/Ativan, Phenobarb

  21. Case con’t • AM BC shows Pseudomonas aer. and VRE • Order written to start CVVH @ 2L/1.73m2/hr, • Calc. clearance: BSA = 0.38m2 (7.24ml/min, or 33ml/min/1.73m2) • What drugs do we care about? • If you can titrate we don’t necessarily care • For this patient antibiotics are going to save her life

  22. Dopamine? Cefepime? Gentamicin? Linezolid? Voriconazole? Pentamidine? Hydrocortsione? Protonix? TPN? Dilaudid? Ativan? So what drugs need adjustment?

  23. Antibiotic Guidelines UM

  24. Linezolid Clearance During CVVHDF • 85 yo 90 kg anuric male in the SICU with documented abdominal VRE infection • Linezolid 600 mg IV q12 • No published literature on CRRT removal • CVVHDF regimen: • dialysate flow rate 2000 mL/hr • mean ultrafiltrate production rate of 775 mL/hr

  25. Linezolid Calculations Half-life, elimination rate, and volume of distribution • Sieving coefficient (SC) was calculated: SC= CE / Cp, Cp = (CA + CV) / 2 • The clearance from CRRT (Cl CRRT) calculated as: Cl CRRT = (QD + QF) x SC • CE = the concentration in the effluent • Cp is the linezolid concentration in the plasma • CA is the linezolid concentration in the plasma drawn from the pre-filter sampling port • CV is the linezolid concentration in the plasma drawn from the post-filter sampling port.

  26. Linezolid Results • Vd = 60L (normal 40-60L) • T1/2 = 7.5-9 hrs during CVVHDF (8hrs) • SC = 0.77– 0.81 (PPB 30%) • ClCRRT = 36.5 mL/min with mean effluent flow rate of 46.2 mL/min • (normal ClR 40mL/min) • No dosage change necessary • First measured linezolid CRRT report • Kraft MK, Pasko DA, DePestel DD, Ellis JJ, Peloquin CA, Mueller BA. Linezolid clearance during continuous venovenous hemodiafiltration: A case report. Pharmacotherapy. 2003 Aug;23(8):1071-5.

  27. Dopamine? Cefepime? Gentamicin? Linezolid? Voriconazole? Pentamidine? Hydrocortsione? Protonix? TPN? Dilaudid? Ativan? So what drugs need adjustment?

  28. Gentamicin pharmacokinetics • This patient weighing 8.5kg receives a gent dose of 21mg (2.5mg/kg) • What peak concentration (mg/L) can be expected? • Volume of distribution of gent is 0.2-0.4L/kg • 0.25L/kg is normal, but in fluid overloaded patients, expect higher values. If 0.3L/kg = • 2.55 Liters = Vd • 21mg/2.55L = 8.2 mg/L assuming no drug removal

  29. Gent kinetics con’t • 30 min after the 21mg dose is done a peak is done = 4.0mg/L • What is the patients actual volume of distribution? • 5.1 Liters = 0.6L/kg (actually double!!!!)

  30. Gent kinetics con’t • Peak was 4.0 mg/L • 12 hours later a random level was done • 1.0 mg/L • What is the half-life (t1/2) of gentamicin? • 4.0mg/L → 2.0mg/L → 1.0mg/L in 12 hours • 6 hour half-life • Ln 4 – ln 1 = kel = 0.115 • 12hrs

  31. Gent kinetics FINAL • Half-life = 0.693 / 0.115 = 6 hours

  32. Dopamine? Cefepime? Gentamicin? Linezolid? Voriconazole? Pentamidine? Hydrocortsione? Protonix? TPN? Dilaudid? Ativan? So what drugs need adjustment?

  33. Phenobarbital case • 2 wof transferred to UM w/ severe CHF w/ AV valve regurgitation and seizure dx • 1/20 had cleft AV valve repair w/ PDA ligation, went on VA ECMO, developed ARF • 1/24 went on CVVHD in-line w/ECMO circuit • Wt 3.45kg (dry), Ht 47cm, BSA 0.21m2 • Qd set at 300ml/hr (~2400ml/1.73m2/hr) • Quf at 69ml/hr (drips + no net loss) • Hemodiafilter = Mini-Plus, 0.08m2

  34. Phenobarbital case • Phenobarbital dose pre dialysis initiation = 25mg q24h = 7.2mg/kg = 35.5mg/L serum concentration • CVVHD started 1/24 • 1/25 Pb = 14.2 mg/L • 1/26 Pb = 9.6 • 1/28 Pb = 13.9 @ 0700 • 1/28 1400 sequential levels done

  35. Phenobarbital case

  36. Drug dosing problems in high volume hemofiltration Most drugs have > 2 compartments (pools) like urea measurements during HD high volume hemofiltration removes drug from peripheral compartment rapidly how fast can drug transfer from deeper compartment? Many drugs rapidly stripped from first pool

  37. Phenobarb case final • SC = 0.44 • ClCRRT = • 2.7ml/0.21m2/min or 22.3ml/1.73m2/min (40) • Vd = 3.24L/kg (0.9L/kg, normal 0.6) • New maintenance dose to maintain level of 25mg/L = • 32.4mg (~10mg/kg) IV q8hrs • Original maintenance dose 25mg q24hrs

  38. Mueller BA, Pasko DA. Artif Organs 2003;27:808-14.

  39. Drug is infused into compartment being filtered/dialyzed reduced ability to distribute into tissues (k12) serum concentrations during infusion higher than usual “therapeutic” serum concentration 6L/hr = 1L/10 min = entire plasma volume/hr Qb 150 ml/min Quf/hd 33 mL/min = 22% of volume removed “first-pass” effect IV drug administration: Drug removed as it is infused

  40. Drug Prescribing in Renal Failureedited by George Aronoff et al • Commonly carried text by pharmacists • http://www.kdp-baptist.louisville.edu/renalbook/ • New edition to come out soon • Recommendations for new drugs • IHD and CRRT recommendations • Pediatric recommendations

  41. Strength of Evidence • Controlled studies in humans or large case series experience • Small Case Series or Human Uncontrolled Trials • Animal or In Vitro Data • Known Drug Characteristics • Vast majority are of this type 58 drugs are A->C

  42. D. “Known drug characteristics“ • These recommendations made by panel of nephrologists and pharmacists • Based on: • Protein Binding Information • Volume of Distribution • Molecular Weight

  43. When in doubt, start here… • Blood flow, filter type are not very important. • Find out • In CVVHD: Dialysate flow rate (ml/hr) • Usually 2 L/1.73m2/hr (33 mL/1.73m2/min) • In CVVH: Substitution Fluid rate (ml/hr) • Usually 2L/1.73m2/hr (33 mL/1.73m2/min) • Add this to patient’s native Cr Cl (ml/1.73m2/min) • This is patient’s new Cr Cl  dose accordingly • Works in most cases…is good enough for initial estimates. Follow up with drug level monitoring.

  44. PCRRT & Roller pump

  45. Future research needed • ECMO/PCRRT • MARS • RAD

  46. CRRT Dosing should not be confusing!

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